Control of allograft rejection in mice by applying a novel neuropeptide, cortistatin

ArticleinAdvances in Therapy 25(12):1331-41 · December 2008with3 Reads
DOI: 10.1007/s12325-008-0121-z · Source: PubMed
The action of cortistatin (CST), a novel cyclic neuropeptide, as an anti-inflammatory factor has been studied, but few investigations have explored the immunomodulatory role of CST in transplantation. In the present study, we examined whether CST affects the alloimmune response in a mouse model of skin transplantation and the effects of CST on T lymphocytes. BALB/c (H-2K(d)) recipient mice (n=70) were divided into seven groups (n=10 per group) and given an intraperitoneal injection of CST or a somatostatin analog, SMS 201-995 (octreotide), on the day of skin transplantation from C57BL/6 (B6) (H-2K(b)) donors. Injections were continued for 7 consecutive days. Groups 1-3 received CST at doses of 0.02, 0.2, or 2 mg/kg, respectively. Groups 4-6 received SMS 201-995 at the same doses. Group 7 was a control group and received injections of phosphate buffered saline. Survival of the allografts was recorded. A semiquantitative reverse transcriptase polymerase chain reaction study of Foxp3 expression and a flow cytometry study of CD4 and CD25 markers of T lymphocytes were conducted to determine whether CD4(+)CD25(+) Foxp3(high) regulatory T cells (T(reg)) were generated in vivo. BALB/c mice given CST (0.2 or 2 mg/kg) had prolonged graft survival (median survival time [MST], 13 and 14 days, respectively; P<0.05 compared with controls). SMS 201-995 at the same concentrations did not have a significant effect on allograft survival (MST, 8 days for both groups). We found more than a twofold increase of CD4(+)CD25(+) T(reg) cells in the CD4(+) T-cell population and the expression of Foxp3 was up-regulated in the CST treatment groups, compared with control and SMS 201-995 treatment groups. In our study, CST induced a significant prolongation in survival time of allogeneic skin grafts and increased the generation of CD4(+)CD25(+) Foxp 3(high) T(reg) cells. These results suggest that CST may become a new modality in controlling allograft rejection.
    • "Recently, many functions of FOXP3 and its influence on the immune system have been elucidated. Tregs influence the development and expression of atopy and the allergic response.9-11 Adaptive FOXP3+ Tregs are essential for establishing mucosal tolerance and for suppressing IL-4 production.17 "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose The pathogenesis of nasal polyposis (NP) is unclear. Eosinophils and mast cells are considered to play important roles in this process. In addition, the levels of Th2-type cells are increased, irrespective of the atopic status of the patient with NP. In this context, we and others have shown high levels of thymus and activation-related chemokine/CCL17, macrophage-derived chemokine, eotaxin, and RANTES in patients with NP. Forkhead box P3 (FOXP3) plays a key role in CD4+CD25+ regulatory T-cell function and represents a specific marker for regulatory T cells (Tregs). Decreased expression of FOXP3 has been reported in allergic diseases. The present study was designed to evaluate the presence and potential roles of Tregs, defined by the expression of FOXP3 protein, in NP. Methods Using immunohistochemistry, we estimated the numbers of FOXP3+ cells in the epithelium and lamina propria of the NPs of 17 patients with chronic rhinosinusitis with NP and the nasal mucosa of 15 patients with allergic rhinitis (AR). The number of FOXP3+ cells in NPs was compared with that in the nasal mucosa of patients with AR, and the numbers of FOXP3+ cells in atopic and non-atopic NP were also compared. Results The number of FOXP3+ cells in the lamina propria of patients with NP was significantly lower than that in the nasal mucosa of the AR patients (2.79 vs. 5.99, P=0.008). There was no statistically significant difference noted for the numbers of FOXP3+ cells between the epithelium of the NP and the nasal mucosa (3.60 vs. 2.39, P=0.180). Furthermore, the numbers of CD4+FOXP3+ cells were lower in NPs than in the allergic nasal mucosa. There was no difference in the number of FOXP3+ cells between the atopic and non-atopic NP patients. Conclusions Fewer Tregs (i.e., decreased FOXP3 expression) are found in NPs than in the nasal mucosa of AR patients. As the severity of eosinophilic, Th2-type inflammation and the levels of inflammatory mediators are much higher in NPs than in the nasal mucosa of AR patients, an inverse co-relationship may exist between these parameters and the number of Tregs. The deficiency of Tregs in NP may account for the more pronounced Th2-type inflammation seen in these patients.
    Full-text · Article · Jan 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Induction of antigen-specific tolerance is critical to prevent autoimmunity, to maintain immune homeostasis, and to achieve transplant tolerance. In addition to their classic role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune and inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. Some neuropeptides that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance. Here, we examine the latest research findings indicating that the role of these neuropeptides in immune tolerance is partially mediated through differential effects on DC functions, which depend on the differentiation and activation states. Importantly, neuropeptides such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and melanocyte-stimulating hormone have demonstrated an ability to induce tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells. The possibility of generating or expanding ex vivo tolerogenic DCs with neuropeptides indicates the therapeutic potential for autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.
    Full-text · Article · May 2009
  • [Show abstract] [Hide abstract] ABSTRACT: There is an increasing understanding of the role of peptides in normal skin function and skin disease. With this knowledge, there is significant interest in the application of peptides as therapeutics in skin disease or as cosmeceuticals to enhance skin appearance. In particular, antimicrobial peptides and those involved in inflammatory processes provide options for the development of new therapeutic directions in chronic skin conditions such as psoriasis and dermatitis. To exploit their potential, it is essential that these peptides are delivered to their site of action in active form and in sufficient quantity to provide the desired effect. Many polymers permeate the skin poorly and are vulnerable to enzymatic degradation. Synthesis of cyclic peptide derivatives can substantially alter the physicochemical characteristics of the peptide with the potential to improve its skin permeation. In addition, cyclization can stabilize the peptide structure and thereby increase its stability. This review describes the role of cyclic peptides in the skin, examples of current cyclic peptide therapeutic products, and the potential for cyclic peptides as dermatological therapeutics and cosmeceuticals.
    Article · May 2010
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